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Understanding ALS (Click here to download text in Word) Understanding ALS (Click here to download text in Word)
Amyotrophic Lateral Sclerosis (more commonly referred to as Lou Gehrig’s disease) is a neuromuscular disease that causes damage to
the nerve cells controlling voluntary muscle movement, also known as motor neurons. It belongs to a group of diseases, known as
motor neuron diseases that affect the motor system. To understand ALS and the spectrum of motor neuron diseases, we will review
the motor system, what the signs and symptoms of motor system damage are, and the different motor system diseases (Table 1).
This will set the stage for an in-depth discussion of ALS including the clinical picture, possible causes, and treatment.
What is the Motor System (Motor system)? - Upper motor neuron (UMN) or corticospinal tract - Lower motor neuron (LMN) or anterior horn cell How can we tell that there is motor neuron damage? - Symptoms of damage to the UMN - Symptoms of damage to the LMN What are Motor Neuron Diseases? - Classification of Motor Neuron Diseases - What other diseases can mimic ALS? Amyotrophic Lateral Sclerosis (ALS) - What is the clinical picture of ALS? What are the different kinds of ALS and variations? - Sporadic ALS - Familial ALS What is a genetic illness and what do I need to understand about genetics? What are the genetics of ALS? Are there other unusual variants of ALS? How is the diagnosis of ALS made? What is the cause of ALS? What kind of treatments are there for ALS? What treatments are there for the disease? What clinical trials are there for people with ALS? How do we choose a medicine to try? What are the recent and ongoing trials in ALS? Are there any other therapies being examined? How can we predict a response to a possible drug? How are the symptoms of ALS managed? What are the medicines used to treat the common symptoms? What is the Motor System? The motor system is a tag team of nerve cells (neurons) that carries messages from the area that controls movement in the brain to the muscle (Figure 1 below). The first part of the motor system carries the signal from the brain to the lower part of the brain (brainstem) and the spinal cord. It is referred to as the upper motor neuron (UMN) or corticospinal tract. The upper motor neuron contacts a second motor neuron referred to as the lower motor neuron (LMN) or anterior horn cell. The LMN then carries the signal to the muscle. The LMNs in the brainstem control the muscles used for speech and swallowing. Involvement of this area is what is referred to as bulbar involvement. The highest part of the spinal cord is known as the cervical cord and motor neurons in this area send messages to the arm muscles and diaphragm (one of the muscles that are important for breathing). The middle part of the spinal cord is called the thoracic cord and neurons here innervate (control) the muscles of the trunk and the muscles of the chest important for breathing. The lowest part of the spinal cord is the lumbar spinal cord and the motor nerves at this level innervate the leg muscles. Back to Top How can we tell that there is motor neuron damage? We can tell that there is motor neuron damage by the symptoms that a person has and by our examination of the motor system (Figure 1 below). When the physician considers motor neuron disease (MND), he/she must evaluate whether there is damage to the motor system; where the damage is-i.e. whether the damage involves the UMN, the LMN, or both pathways; and whether there is any indication of damage outside the motor system (which could indicate a diagnosis of something other than MND). Sometimes we also need a special test called the EMG-NCV (Electromyogram and Nerve Conduction studies) to help us to detect damage to the lower motor neurons and to exclude more treatable diseases such as motor neuropathy with multifocal conduction block (See the section on classification of motor neuron diseases and the section on differential diagnosis). Symptoms of damage to the UMN include stiffness, cramps, slowness of movement, laughing or crying too easily (termed pseudobulbar affect), nasal slow speech, and sometimes urgency of urination. The signs of upper motor neuron damage on exam include an increase in muscle tone or stiffness with resistance to movement called spasticity, increased reflexes (when the knee, ankle, inner elbow and arm are tapped with the reflex hammer), and abnormal reflexes (this includes an increase in chin movement with a tap called a jaw jerk, the presence of a Babinski sign where the big toe goes up instead of down when the sole of the foot is stimulated, and the presence of increased finger flexion on the appropriate stimulus). Symptoms of LMN damage include weakness, thinning of the muscles or atrophy, twitching of the muscles or fasciculations, and cramps. The examination demonstrates weakness and atrophy with fasciculations and a decrease in tone with absent or diminished reflexes. The EMG will demonstrate damage due to LMN loss in the weakened muscles and may also show changes in muscles that are still strong. NCV should be normal. However, these studies are important because they help to detect motor neuropathy with or without conduction block in people with mainly LMN damage. Those individuals may have a motor neuropathy that is treatable. It is very important to understand that the presence of motor neuron damage does not mean that someone has ALS or any other motor neuron disease. We must first rule out any other cause of the motor neuron damage. Below is a discussion of the differential diagnosis of ALS (i.e. the other things to consider).  Figure 1. The motor system is comprised of the upper motor neuron (corticospinal tract) and the lower motor neuron (anterior horn cell). Back to Top What are Motor Neuron Diseases? Motor neuron diseases (MND) damage the motor system. They can affect either the upper motor neuron (UMN), the lower motor neuron (LMN), or both. These diseases are named for the part of the motor system they involve. In ALS both the UMN and the LMN are damaged. Table 1 lists the more common diseases, listed by which portion of the motor system they involve. Table 1: Classification of Motor Neuron Diseases • UMN: – Primary Lateral Sclerosis (PLS) • Variants include Bulbar Palsy – Familial Spastic Paraparesis • LMN: – Spinal Muscular Atrophy (SMA) – Progressive Muscular Atrophy – Monomelic amyotrophy (one extremity with slow progression) – Brachial amyotrophic diplegia (progressive weakness of both arms with no bulbar or respiratory involvement) – Motor Neuropathy with or without conduction block * – Kennedy’s Disease (an hereditary disease of the androgen receptor) • UMN and LMN: – Amyotrophic Lateral Sclerosis (ALS) • Variants include Bulbar Palsy * Motor neuropathy with conduction block is an important disease as it is treatable. It is an autoimmune disorder characterized by “conduction block” on Nerve Conduction studies, predominantly lower motor neuron clinical picture, the presence of anti GM1 antibodies (a blood test), and elevated spinal fluid protein. It responds to intravenous gamma globulin. Back to Top The classical MNDs include: Amyotrophic Lateral Sclerosis – is the ALS originally described by Charcot and thus it is often called Charcot’s disease in Europe. Classical ALS is a distinct syndrome characterized by a combination of UMN and LMN signs and symptoms without other neurological problems and no other explanation but a motor system disorder. In approximately two thirds of patients with ALS, the disease takes this form. Progressive Muscular Atrophy (PMA) – constitutes roughly 8 to 10 percent of patients with sporadic ALS. PMA is sometimes called Aran-Duchenne type of motor neuron disease (MND). The initial symptoms are manifestations of LMN involvement of the spinal cord and, in a later stage, of the lower brainstem. If UMN signs do not develop within two years, the disease is likely to remain PMA. Primary Lateral Sclerosis (PLS) – was first described by Erb in 1875. The clinical signs of PLS consist only of UMN signs. It is the rarest of all the forms of ALS. Back to Top What other diseases can mimic ALS? When we deal with the potential diagnosis of ALS, it is essential to exclude treatable diseases and other less severe MNDs, although they are very rare. A good motto is: Leave no stone unturned! If a person has motor neuron damage, there are certain findings which clearly suggest another diagnosis or an additional problem besides a MND. These findings include: sensation problems, significant bladder problems, or peripheral nervous system problems. A list of some of the more important diagnoses to consider can be found below and in Table 2. Polyradiculopathy/myelopathy – A combination of chronic cervical and lumbosacral polyradiculopathy (pinching of the nerves as they exit the cervical and lumbar spine ) and spondylitic myelopathy (bony overgrowth in the spine that pinches the spinal cord) can cause a variety of upper and lower motor neuron signs without sensory symptoms and can closely resemble ALS. Post-polio Syndrome – Post-poliomyelitic muscular atrophy is characterized by progressive muscle atrophy and weakness that develops at least fifteen years after recovery from acute polio. It usually affects the muscles previously affected by polio and looks like a LMN disorder. In general it does not cause UMN signs. Motor Neuropathy with Anti-GM1 Antibody – Motor neuropathy with high anti-ganglioside antibodies1 is manifested as predominantly lower motor neuron disease with multifocal conduction block on EMG-NCV studies. Conduction block are areas along the motor nerves where the electric potential is not carried as well (i.e. blocked) resulting in a decrease in the amount of response detected over the muscle. This condition is potentially treatable with immune system modulating drugs. 1 An antibody is a protein made by the immune system. This protein is designed to attach to and help destroy a particular “antigen”. Antigens are proteins or parts of proteins that are usually foreign. In autoimmune diseases, the antigen is not foreign but rather part of your body; the result of which is your immune system attacking your own body. In this case the antigen is the ganglioside on the motor nerve and the covering to the nerve that is being attacked by the immune system. MND and Gammopathy/paraproteinemia – Monoclonal gammopathy (an excess of a single immune system protein) is more frequently found in patients with ALS than in the general population of similar age groups. IgM paraproteinemia also is reported in rare cases of motor neuron disease of predominantly LMN. Evidence that some patients with ALS have monoclonal gammopathy, positive anti-GM1 antibody, or both led to a hypothesis that ALS is an unconventional autoimmune disease. Heavy Metal Intoxication – Lead intoxication may cause motor neuropathy, whereas chronic mercury intoxication is reported to produce upper and lower motor neuron signs along with other CNS manifestations. Hexosaminidase-A Deficiency – Adult hexosaminidase-A deficiency (an enzyme deficiency responsible for Tay Sachs Disease) is associated with nervous system problems. It can causes pure LMN disease, which mimics spinal muscular atrophy, or both LMN and UMN with a resemblance to ALS. In this rare condition there are almost always other neurological findings in addition to the damage to the motor system. When there are UMN signs, either alone or with LMN signs; spine disease, hyperparathyroidism, hyperthyroidism, adrenoleukodystrophy, mitochondrial disease, and spastic paraparesis should be ruled out. Furthermore, Lyme disease, vasculitis, and certain multi-system diseases should be investigated as they can include motor nerve involvement and mimic ALS. Table 2: Differential Diagnosis A. Pure LMN a. Spinal Muscular Atrophy b. Progressive Muscular Atrophy c. Inflammatory Neuropathies i. CIDP ii. Multifocal Conduction Block d. Motor Neuropathies i. Associated with tumors ii. Associated with metabolic problems 1. porphyria 2. gangliosidoses (including Tay Sachs variants) iii. Associated with toxins 1. lead iv. Associated with immune system abnormalities 1. monoclonal gammopathies and myeloma v. Associated with vasculitis e. Electrical Injuries f. Viral Infections i. Polio ii. HIV B. Pure UMN a. Primary Lateral Sclerosis b. Familial Spastic Paraparesis c. Carrier of Adrenoleukodystrophy d. Multiple Sclerosis e. Mitochondrial Diseases f. CNS vasculitis g. Leukodystrophies h. Vitamin E Deficiency (Usually with sensory) i. B12 Deficiency (usually with sensory) C. UMN and LMN a. Amyotrophic Lateral Sclerosis b. Spine disease c. Vasculitis d. Mitochondrial disease e. Lyme Disease f. Endocrine Dysfunction g. Thyroid or Parathyroid disease Back to Top Amyotrophic Lateral Sclerosis (ALS) What is the clinical picture of ALS? ALS is a MND characterized by damage to both the UMN and the LMN (see What is the motor system? and How can we tell_Motor_Neuron_damage? above). ALS generally affects people between 55 and 75 years of age although all ages can be involved. The prevalence (how many people have the disease at one time) rate is about 4 per 100,000 while the incidence (how many new cases occur in a time period) is about 1 per 100,000 new cases each year. There is a male-to-female ratio of about 2:1. The symptoms of ALS vary from one person to the next. Symptoms reflect weakness and thinning of muscles due to the involvement of the LMN as well as stiffness from the UMN involvement. Onset can begin in the muscles that are innervated by the bulbar neurons (speaking, swallowing) or in muscles innervated by nerve cells in the spinal cord causing weakness in one arm or one leg. A person newly diagnosed with ALS may trip, drop things, slur their speech, twitch, and laugh or cry uncontrollably. The person may also experience abnormal fatigue of the arms or legs and muscle cramps. Walking and activities requiring the hands may prove more difficult for a person with the disease. In 20% of ALS cases, speech and swallowing begin to decline first. Another 40% have symptoms in the arm first while the rest of people experience problems due to leg involvement. Over time the disease spreads from one area to another and gradually the people living with ALS will lose movement in muscles throughout the body, including the muscles of breathing. While the average lifespan is about 36 months, it is important to recognize that 20% of people live for five years and 10% of patients live for 10 years. There are some restricted variants of the illness in which there is no spread outside of the initial area of involvement. These restricted variants include Bulbar palsy in which speech and swallowing are involved and some focal amyotrophies in which only one extremity is involved with either little or no progression. Back to Top What are the different kinds of ALS and variations? There are both sporadic (no family history) and genetic (inherited) forms of disease described below. Sporadic ALS Classical ALS Classical ALS is a distinct syndrome characterized by a combination of UMN and LMN problems and occurs in about two thirds of people with ALS. Progressive Bulbar Palsy (PBP) – was originally described by Duchenne in 1860. In approximately 25 percent of people with ALS, the initial symptoms begin in muscles innervated by the lower brainstem that control articulation, chewing and swallowing. Sometimes the disease remains in this form for years, but usually it progresses to generalized muscle weakness, that is, to ALS. When the disease is strictly limited to the bulbar muscles clinically and electrodiagnostically, it is PBP, not classical ALS. Whether the above forms of sporadic ALS represent a spectrum of the same disease or whether they are in fact distinct is not yet known. Back to Top Familial ALS What is a genetic illness and what do I need to understand about genetics? In some instances, ALS runs in the family, i.e. it is genetic. This happens in 10% or less of all people with ALS although it is likely that your genetic makeup may play a role in your susceptibility to disease. A nice overview of genetics in lay language can be found on the MDA website at http://www.mdausa.org/publications/gen_faq.html. Briefly, all of our genetic information is carried on chromosomes that are strands of a chemical called DNA (deoxy ribonucleic acid). DNA contains a sequence of information in the form of building blocks called nucleotides. These DNA strands are located in the nucleus of every cell in the body and are organized in pairs. There are 22 pairs of chromosomes called autosomes and an additional pair of sex chromosomes that determine whether you are a male or female. For each pair of chromosomes, you have inherited one chromosome from your mother and one from your father. The DNA of chromosomes is organized in a sequence of nucleotides that code for genes. Genes are organized like beads on a necklace, and each gene contains information that tells the cell how to make a particular protein. The chromosome also contains regions that control the production of the protein and respond to events in the cell. In order to make a protein, information from the DNA is first “transcribed” or converted into RNA (Ribonucleic Acid) as a message that will leave the nucleus and travel into the cell. We call this messenger RNA (mRNA). This message provides the information to the cell about how to make the protein. Every three nucleotides in the message RNA tells the cell one amino acid (these are the building blocks of any protein) in the protein. The sequence of nucleotides in the RNA determines the sequence of amino acids in the protein and provides the code for what sequence of amino acids to string together to create the specified protein. The mRNA is used as a template by the cell to make the protein - i.e. translate the information. In genetic illnesses, there are abnormalities in the genetic code of DNA (called mutations) that result in problems with protein production. In some cases no protein is made, in others an abnormal protein that is rapidly degraded is made, in others an abnormal protein that malfunctions can be made, and finally there may be problems in the regulation of normal protein production. Genetic problems can be inherited in several ways. A disease may be dominant or recessive. If it is dominant, then only one of the two copies of the gene is abnormal, yet it results in disease. In recessive diseases, there needs to be a problem in each of the two genes that are inherited from your parents. Each parent would be a carrier and not have the disease while the child who has inherited a damaged gene from each parent would show the disease. Most X-linked mutations affect males (who only have one X chromosome, paired with a Y chromosome) but rarely affect females (who have two X chromosomes, one of which usually doesn't have the mutation). However, X-linked mutations can sometimes affect females. Back to Top What are the genetics of ALS? Familial ALS cases comprise 5 to 10 percent of all cases of ALS. Familial ALS (FALS) is inherited as an autosomal dominant trait. Almost 20 % of people with FALS have damage (called a mutation) in the gene that codes for the protein Cu/Zn superoxide dismutase (SOD 1) located on chromosome 21. There are no differences between familial and sporadic ALS on neurological exam except for occasional sensory loss in people with FALS. Other genes that, when damaged, can lead to ALS, have been identified on chromosomes 2, 9, 15, 18 and the X chromosome. We expect to find more genes as well as genes that can modify disease through research and genetic studies in families and siblings of people with both sporadic and familial ALS. In addition to directly inheriting a gene that causes ALS, there are also susceptibility genes. In this case, a particular gene structure is inherited that seems to alter the risk of developing ALS but is not directly causal. Some genes that, when constructed in a certain variation, can modify susceptibility to ALS have already been identified. These include the gene for vascular endothelial growth factor- VEGF, the gene for iron processing-HFe, and a gene responsible to help metabolize organophosphate insecticides-POMC. Recently there have been more modifying genes that have been implicated although additional work is ongoing to identify them. Back to Top Are there other unusual variants of ALS? Western Pacific ALS Western Pacific ALS occurs primarily on the island of Guam, the Kii Peninsula of Japan, and New Guinea. The people on Guam have the same clinical characteristics seen in sporadic ALS and also can have a dementia and Parkinsons like illness. The illness on Guam is the first to be tied to a toxin, the cycad nut. This nut contains a compound that is toxic to nerve cells called BMAA and is similar to glutamate (see below under the section What is the cause of ALS?). The nut is eaten by the fruit bat which was a delicacy among the Chamorro population of Guam. This allowed a very high concentration of the toxin to be eaten and it has been postulated but not proven, that this caused the disease. The fruit bat was eaten to extinction and now fruit bats for consumption are imported, the disease has all but disappeared! Juvenile ALS Rare cases of adolescent motor neuron disease that are clinically indistinguishable from ALS have been reported. Onset is between ages twelve and sixteen. Although ALS can occur at young ages, these cases are probably different from sporadic ALS. Hiramaya Disease This is a rare disorder seem in young men. In this variant there is localized atrophy of one arm associated with increased reflexes implicating the presence of upper and lower motor neuron damage (See How_can_we_tell_Motor_Neuron_damage?). However, the disorder is a problem at the junction between the cervical spine and the skull where there is pressure on the cervical spinal cord. In order to detect it, MRI of the neck needs to be performed in different positions including neck flexion and extension. Back to Top How is the diagnosis of ALS made? The diagnosis is made by identifying damage to only the motor system, with damage to both the upper and lower motor neurons.2 In addition, all other possible causes of that damage must be excluded and there must be progression of the weakness over time with involvement of multiple areas in the nervous system. The areas that are evaluated include the bulbar region (speech and swallowing), cervical region (arms, diaphragm), thoracic region (muscles of breathing), and the lumbar region (legs). 2 An extended discussion of the motor system and the signs and symptoms indicating damage to it can be found above in the sections entitled: What is the Motor system? and How can_we tell Motor Neuron damage?. Back to Top What is the Cause of ALS? The cause of ALS is not known (see Table3: Possible Causes of ALS below). However it is likely that ALS is a complex multi-system disease with several mechanisms that cause the death of motor neurons. Any one of these mechanisms or a combination of several may be responsible for the disease. Furthermore as pointed out in the section entitled “What are the genetics of ALS?”, there are likely to be genes and hereditary factors that will modify the disease and susceptibility. These mechanisms and the pathways influenced by modifying genes provide targets for therapeutic strategies. The most important mechanisms are outlined below. Table 3: Possible Causes of ALS • Defective glutamate metabolism • Free radical injury • Mitochondrial dysfunction • Gene defects • Programmed cell death or Apoptosis • Cytoskeletal protein defects • Autoimmune and Inflammatory mechanisms • Accumulation of protein aggregates (clumps) • Viral infections Defective glutamate metabolism: To date, one of the most robust theories of pathogenesis of ALS is excito-toxicity of glutamate. Glutamate is a common chemical in the nervous system used for signaling between neurons. While it is important for normal nerve cell function, it is toxic in excess. There is evidence of increased glutamate in ALS patients and in ALS mice and this in turn may be responsible for nerve cell death. The increased glutamate may result from either abnormal transport of glutamate out of the nerve cell environment or increased release of glutamate from nerve cells. To date, there is some evidence that the transporter responsible for removing glutamate from the nervous system may be altered and/or the process for making the transport protein damaged. Free radical injury and oxidative stress: Free radicals are molecules with unpaired electrons. These molecules are unstable and liable to damage cellular structures including proteins and lipids (fats) within nerve cells. Free radicals are a normal part of cellular life and cells are usually able to neutralize them and keep their numbers in check. However, in ALS, free radicals build to toxic levels and damage cells, through an attack process called oxidative stress. It is of interest that 20% of Familial ALS patients have mutations in SOD1, an enzyme that detoxifies oxygen free radicals. There is evidence that there are higher levels of protein carbonyl groups (caused by oxidative stress to proteins) and oxidized nucleic acids in brain tissue from patients with sporadic ALS. Mitochondrial dysfunction: Free radicals are also produced in the powerhouse of the cell called the mitochondria. Mitochondria and its genetic material are especially sensitive to the oxidative damage from free radicals and may be one of the earliest sites of damage in ALS and in familial ALS. This in turn results in lower energy production by the nerve cell and less ability to do its job. Gene defects: Ten percent of ALS is inherited and 20% of these patients carry a mutation in the Superoxide Dismutase Gene (SOD1). In addition there may be other genetic factors that play a role in the cause of ALS. One such factor is the level of the protein VEGF (vascular endothelial growth factor) that is made depending on the structure of a persons’ VEGF gene. Another genetic factor recently implicated is the gene for the iron processing protein HFe. Other factors include how the genetic message (mRNA) for the glutamate transport protein is processed and the presence of mutations in the gene for the structural protein called neurofilament. The possible genetic contribution to the development of ALS is an active research area. Programmed cell death (apoptosis): ALS may be due to an early death of motor neurons or a premature initiation of programmed cell death or suicide (called apoptosis). Cytoskeletal protein defects: Neurofilaments provide a scaffold structure to maintain the long process (called the axon) that extends from the cell body of nerve cells out to the muscle or down the spinal cord. These filaments also provide the railroad tracks to transport important molecules up and down the axon. It has been shown that neurofilaments accumulate in the nerve cell body and processes (called axons) in ALS as well as animal models. Autoimmune dysfunction/ Inflammatory Damage: There is a higher incidence of immune disorders and abnormal immune system made proteins (including monoclonal gammopathies and anti-GM1 antibodies that were discussed above) in people with ALS. Immune attacks on the nerve cells could trigger increased intracellular calcium and motor neuron degeneration. In addition, it has been demonstrated in both the mouse model of ALS that carries the mutated SOD1 gene and in people with ALS that there is inflammation in the brain. Special inflammatory cells in the brain called microglia are activated and there is an increase in proteins such as COX 2 that produce a state of inflammation by increasing the production of inflammatory mediators. These mediators are called cytokines and some are protective while others can damage cells. The balance of the types of cytokines produced will determine if the overall effect of inflammation is good or bad! Protein aggregation: This is the clumping of proteins that are misshapen either because of damage from ongoing cell processes or through the inheritance of an abnormal structure in genetic disorders. There have been abnormal clumps of protein identified in mice with ALS that carry the mutated gene for SOD 1 as well as other animal models of motor diseases. These clumps of protein may interfere with normal motor nerve cell functions leading to cell death. Virus: The idea that viral illness may play a role in ALS comes from several lines of evidence. First, polio virus causes a motor system disease that affects the lower motor neurons. Secondly, genetic material from a type of virus called echovirus was found in the spinal cords of ALS patients. Finally, HIV (human immunodeficiency) virus can cause an ALS-like syndrome that improves with antiviral drugs. Back to Top What kind of treatments are there for ALS? While we do not yet have a cure for ALS, there is treatment. First, there is medicine, Rilutek (Riluzole), which slows the disease progression by decreasing glutamate levels. In addition there are many ongoing Clinical Trials that use agents that target possible causes of the disease. Furthermore, advances in the aggressive treatment of respiratory complications of ALS with noninvasive ventilation and respiratory management as well as aggressive nutritional intervention have provided significant improvements in the morbidity and morality. Finally, there are symptom specific treatments and a multidisciplinary approach utilizing occupational and physical therapists, speech therapists, nutritionists, and nurse specialists that have led to improved quality of life and maximization of function in the person living with ALS. A review of disease specific treatment, clinical trials, and symptom management follows. What treatments are there for the disease? Rilutek (Riluzole) The only drug approved to specifically treat ALS as of now is Rilutek. Studies performed showed that Rilutek helped to protect nerve cells from damage likely by reducing the amount of glutamate in the nervous system. It is important to understand that Rilutek will not restore any loss of function prior to the start of treatment. It only slows progression. The recommended dosage for Rilutek is 50mg (one tablet) every 12 hours. The medication should be taken the same time every day such as every morning and night. Rilutek should be taken at least one hour after meals. The most common side effects of Rilutek are weakness, nausea, dizziness, headache and elevation of liver enzymes. If there is nausea, your doctor may recommend that the medicine be taken with meals. It is not recommended that you smoke or drink excessive amounts of alcohol while taking this medication. Smoking may decrease the amount of Rilutek in your bloodstream. Alcohol may contribute to elevated liver enzymes and may cause an increase risk of liver problems while taking Rilutek. Back to Top What clinical trials are there for people with ALS? How do we choose a medicine to try? The key to selecting possible therapeutic agents lies in the understanding of a disease. To date the cause of ALS is not known but several theories have been proposed and there is experimental evidence to support each theory (See the section: What is the cause of ALS?) There may be interplay of one or more of these mechanisms that lead to nerve cell death in ALS. Furthermore there may be genetic factors that are important to the predisposition to develop disease with the right provocation. The mechanisms of neuronal death in ALS that have been theorized include: defective glutamate metabolism, free radical injury, mitochondrial dysfunction, gene defects, programmed cell death (apoptosis), cytoskeletal protein defects (including neurofilament abnormalities), autoimmune dysfunction, and viral infections including retroviruses (HIV). These proposed causes of ALS have provided targets for drug therapies. Below we discuss what medications have been tried based on each of the theories. Back to Top What are the recent and ongoing trials in ALS? Anti-glutamatergic agents (Table 4: Antiglutamate Strategies: There have been several anti-glutamatergic agents that have been examined in ALS and in fact the one drug that has prolonged survival is an anti-glutaminergic drug, riluzole. Riluzole inhibits the release of glutamate and has prolonged the survival in the ALS mouse model. It has now been tested in two clinical trials in humans. There are now several other antiglutamate drugs that have been tested. Topamax, neurontin, low dose lamictal (lamotrogine), and dextromethorophan have shown no benefit. A drug by Lilly was promising but has not yet gone to trial (LY300164) or Talampanel. There is now an investigator driven effort to bring Talampanel to trial. Another drug that likely modifies glutamate by altering the transport protein for it is Ceftriaxone. A clinical trial of Ceftriaxone has recently been initiated. Finally, NAALADase ( N-acetylated alpha linked acidic dipeptidase) is a good candidate drug since it may simultaneously reduce glutamate production and decrease its release in the brain. However there have been no studies in humans yet.
Back to Top Anti-apoptosis agents: Trophic (growth inducing) factors that help to protect neurons from cell death have been studied in patients with ALS. To date, these neurotrophic factors in ALS have not shown clear benefits. There are ongoing trials of IGF-1, or Myotrophin, in process. Another agent that may block apoptosis is now in a large Phase III trial headed by Dr. Paul Gordon at Columbia University; the antibiotic minocycline. This agent is an antibiotic that protects the mitochondria and helps to block the release of the protein Cytochrome C from the mitochondria (the energy powerhouse of all cells). Cytochrome C provides the signal to initiate cell death and minocycline appears to block this signal. It was recently shown to be effective in ALS mice. TCH346 is a novel compound recently investigated as a treatment for ALS which did not have any efficacy. TCH346 interacts with a protein enzyme (GAPDH) which has recently been implicated in programmed cell death and this interaction seems to be important for the effect of TCH346 in models of nerve degeneration. TCH346 prevents the degeneration of neurons in a variety of tissue culture and animal models of programmed cell death. These preclinical findings provided the rationale for study of TCH346 in ALS. Neurotrophins or Neurotrophin stimulating Agents: Neurotrophic factors are chemicals in the body that preserve and nourish nerve cells including motor nerve cells. One possible way nerve cells die in ALS may relate to a lack of neurotrophins or an altered response by neurotrophins. These substances block or delay cell death or apoptosis. To date, neurotrophic factors including Xaliproden, BDNF, CNTF, Growth Hormone, and GDNF have not shown clear benefits. IGF1 (brand name Myotrophin) is a neurotrophic factor and like other neurotrophic factors, IGF1 has shown some protective effects on nerve cells in laboratory experiments. Previously Myotrophin was tested in patients with ALS in Europe and the United States but results of these trials conflicted, with the U.S. patients showing some benefit, while negative results were found in the European patients. The differences have been attributed to study design problems, and the U.S. Food and Drug Administration has asked for a third clinical trial to resolve the issue of Myotrophin’s safety and effectiveness in ALS. The present study is a longer study (two years) than the previous studies and will assess more direct measures of muscle strength. The objective of this study is to determine whether Myotrophin slows the progression of weakness in ALS. People may not notice a difference in symptoms, as Myotrophin is not expected to halt or reverse the weakness in ALS, but rather to slow its course. This is a double-blind, placebo-controlled study. The coordinating center is at the Mayo Clinic. Buspirone is a commonly used antianxiety agent that is generally well tolerated. Its mechanism of action for treating anxiety is unknown but it has high affinity for serotonin receptors (special docking sites on brain cells). Buspirone may also mimic or stimulate the activity of endogenous (inside the body) neurotrophins (nerve-nourishing substances), such a nerve growth factor (NGF) and brain-derived growth factor (BDNF). Because of these actions, preliminary studies were conducted in mice with ALS. Initial results demonstrated improvements in pulmonary function compared to untreated littermates. It is theorized that buspirone treatment will result in short-term benefits in pulmonary function in patients with ALS. A double-masked, randomized, placebo-controlled clinical trial in which patients are assigned to receive buspirone or placebo has been initiated at Johns Hopkins University. Pulmonary function and respiratory symptoms will be followed over the course of this study.
Back to Top Anti-oxidative agents: There have been several trials of antioxidants and mitochondrial buttressing agents as treatments in ALS. First several antioxidants have been tried in small studies, Vitamin E, N-acetylcysteine and deprenyl. Recently creatine has demonstrated neuroprotection in a mouse model of ALS but failed to show an effect in two recent trials in people with ALS. Co-enzyme Q10 has moderate benefit in mouse model of ALS and is also being tried in ALS patients in an ongoing clinical study at Columbia University. There will be a new trial of high doses of a liquid preparation of co-enzyme Q10 that has better absorption starting in the fall. Tamoxifen, an agent used in breast carcinoma patients, may also help to protect mitochondria and Phase II clinical trials have shown promising results. Aeolus Pharmaceuticals recently completed the initial Phase I clinical trial of their investigational drug, AEOL 10150, in people living with ALS. AEOL 10150 is part of a new class of small molecule catalytic antioxidants that destroy oxygen-derived free radicals. In pre-clinical animal studies, the catalytic antioxidants have been shown improve survival in ALS mice. Pramiprexole, an anti-Parkinsonian agent, has anti-oxidant actions and is now in a small Phase II trial in ALS patients. Hyperbaric oxygen has shown promising effects in a small group of patients as well. Arimoclomol is an agent that increases a neuroprotective protein called heat-shock protein. This provides both an anti-oxidant action and neurotrophic action. A Phase IIa trial has just been completed and a wider, efficacy directed Phase IIb trial is to start over the next 6 months.
Back to Top Agents that alter the Immune response: Based on evidence that ALS may in part be due to autoimmune mechanisms, Dr. Stanley Appel at Baylor, is examining the effects of bone marrow transplantation in ALS. Recently, the clinical trial of Celebrex has been completed but showed no efficacy. Celebrex inhibits an inflammatory modulating protein called COX 2. COX 2 is present in the spinal cord and may play a role in releasing glutamate from cells in the spinal cord and also may promote oxidative damage to nerve cells. It has been shown that COX 2 expression is increased in the ALS mouse model and in spinal cords of ALS patients. COX 2 inhibitors have been shown to decrease glutamate toxicity in culture models and Celebrex, increased the survival in ALS mice. Other COX 2 inhibitors (Nimesulide) may come to trial in the future. Other drugs that modify the inflammatory reaction in the brain include minocycline, Copaxone, Thalidomide, Lenolidomide, Celastrol and ONO 2506 (an analogue of depakote). These drugs capitalize on strategies to decrease the activity of the cells in the nervous system that cause damage at times of inflammation including microglia and astrocytes. Alternatively, they may block the molecules released by these cells responsible for the damage including molecules like TNF alpha or COX 2. Minocycline modifies the response of microglia, an inflammatory cell in the nervous system. Copaxone, a drug that modifies the inflammatory response in multiple sclerosis has shown neuroprotective effects in the mouse model of ALS and is presently in a Phase II trial in ALS patients. Thalidomide and its less toxic analogue lenolidomide, inhibit inflammation and TNF alpha. Thalidomide worked in the mouse model of ALS and a small Phase II trial is underway in people with ALS using the less toxic analogue of thalidomide, lenolidamide. ONO 2506 has a similar structure to depakote, an FDA approved anti-seizure medication. These drugs modify astrocyte reaction and decrease glutamate release. The ONO 2506 compound recently completed Phase II testing and there is a Phase III trial starting in Europe. Depakote is in a small Phase II study in the US. Celastrol is both an anti-inflammatory and anti-oxidant because it that blocks TNF alpha and IL1 beta molecules which increase inflammatory damage to nerve cells and decreases nitrous oxide (NO) which causes oxidative damage. Nimesulide is a potential drug candidate because it can inhibit COX 2. In animals it decreased COX 2 and slowed motor loss.
Anti-viral agents: The human immunodeficiency virus (HIV), which causes AIDS (acquired immunodeficiency syndrome), can cause an ALS-like syndrome that improves with treatment with antiviral drugs. Given this recent report of an ALS like illness in HIV infected patients a trial was carried out at Beth Israel Hospital with the antiviral agent Indinavir. Unfortunately, there was no effect on disease. Back to Top Are there any other therapies being examined? Oxandrolone: Oxandrolone is a synthetic steroid of the “anabolic,” or tissue-building, type. It is similar in structure to the male hormone testosterone. Oxandrolone was tested in 12 people with ALS in an open label trial by Dr. Jeffrey Rothstein. It appears to have prevented a decrease in strength in some muscle groups, although it did not slow the weight loss associated with the disease, which was the primary question for this trial. The number of participants was not large enough for any definitive conclusions but provided enough information to consider Oxandrolone in conjunction with other compounds. It was well tolerated with few side effects. Marinol: Dronabinol (brand name Marinol) is a marijuana-derived compound approved by the U.S. Food and Drug Administration for treatment in AIDS and cancer. Dr. Deborah Gelinas and Dr. Robert Miller from the MDA/ALS Center at California Pacific Medical Center in San Francisco have examined the drug in 20 people with ALS. During the three-month study the drug was well tolerated and there were improvements in sleep, appetite and spasticity (muscle tightness) noted. The researchers feel that the compound merits further study for its possible symptom relief and perhaps as a neuroprotective agent. Stem Cell Safety Trial: A procedure in which bone marrow stem cells were taken from seven Italian ALS patients and implanted into their spinal cords appears to be safe and well tolerated, physician-investigator Letizia Mazzini announced. Establishing safety was the purpose of the trial. The seven patients, who apparently received stem cell transfers in October 2001, had no major problems, with the exception of pain after surgery. Scriptaid: inhibits aggregation Trehalose: Trehalose is a natural disaccharide used to prevent protein denaturation in freeze dried products and may prevent formation of mutant SOD aggregates. Phenylbutyrate: Phenylbutyrate is used for hyperammonemia. It inhibits histone deacetylase and leads to increased gene transcription. It extended animal life by 21.9% in trials. Tamoxifen: Tamoxifen inhibits protein kinase C, which mediates inflammation, It extends life in viral induced motor neuron death. Prolonged survival in Phase II study at 10-20-30-and 40 mg.
See Clinical Trials under Center of Hope for information on trials here. Back to Top How can we predict a response to a possible drug? While I have discussed the latest clinical trials in patients with ALS, one major advance in recent years has been the development of the transgenic mouse model of ALS. This mouse carries a mutated human SOD (Superoxide dismutase) gene. This mutated gene was identified in some patients with the hereditary form of ALS. The mice develop a motor system disease and die at around 125 days of age. This model has provided an animal model to study the disease and also to test new drugs. There have been over 50 agents now tried in the model. Its usefulness will be determined by the correlation of drug efficacy in the model compared to results in humans. Recently a triple-drug cocktail consisting of riluzole, minocycline and nimodidpine was tested in the animal model. Minocycline, an antibiotic believed to inhibit apoptosis (cell suicide), has already been shown to extend survival in SOD1 mice by about three weeks when given alone and is being tested in ALS patients (see above under upcoming clinical trials). Nimodipine works by blocking the entry of calcium into neurons — thought by some ALS experts to be an early event in motor neuron death. Riluzole (Rilutek), the only FDA-approved drug for treating ALS, works by inhibiting the release of glutamate by brain cells. It extends life by just a few weeks in mice with the disease and by a few months in people with ALS. SOD1 mice given all three drugs when they were in the early stages of ALS lived about six weeks longer than untreated mice did. Since all three drugs have FDA approval for treating different diseases, the triple-drug cocktail could be fast-tracked into clinical trials. Back to Top On the Horizon: Rapid Screening of FDA Approved Compounds: While the animal model is an exciting advance for both use in clinical evaluation and basic research into mechanism, the average clinical trial in the animal takes 6-9 months. Therefore, there has been an increasing interest in the development of rapid throughput assays for new drugs that could predict clinical response in ALS by patients in days rather than months. This has led to a large effort coordinated by the National Institutes of Neurological Diseases and Stroke (NINDS) to find treatments for some of the most devastating neurological diseases, including ALS, Huntington’s disease, Parkinson’s, spinal muscular atrophy and spinal bulbar muscular atrophy. There are nearly 30 laboratories across the country — collectively known as the Neurodegeneration Drug Screening Consortium (NDSC) — using a variety of methods to test the effects of more than 1,000 chemicals, most of which are FDA-approved drugs. These methods involve the development of assays that are rapidly performed and test drug effects on possible pathologic mechanisms relevant to the various diseases. For instance, the assays for the toxicity of glutamate have been included since glutamate excitotoxicity may play a role in ALS. If a compound mitigates toxicity in an ALS-specific assay, this may predict a response in people with ALS. Furthermore, there are several ALS specific assays included in the screening and compounds that work in more than just one assay are even more promising. To date, across all of the laboratories involved in the screening program there were seven chemicals that were hits in two or more of the ALS-specific tests, indicating that they might work against key parts of the disease process. The next steps for development is to test the drugs that work in ALS specific tests in the transgenic mouse model. If the results are promising, these compounds can be rapidly taken to clinical trial as they are already FDA approved for other uses. In fact, the first trial of one of the “hits” was scheduled to start early in 2005 with a clinical trial of Ceftriaxone. This will be given intravenously and daily. Back to Top How are the symptoms of ALS managed? While there is no cure for ALS at present, there is treatment. First, Riluzole slows disease progression and improves outcome. However, the mainstay of clinical management of ALS is focused primarily on symptom relief. Treatment of symptoms increases the quality of life for people living with ALS by reducing complications and increasing comfort. Furthermore, aggressive respiratory and nutritional intervention can improve both the morbidity and mortality from ALS. What are the most common symptoms?
We have evaluated over four hundred and sixty seven ALS patients at six ALS centers, including the MDA/ALS Center of Hope at Drexel, to determine what symptoms are most commonly experienced, how bothersome they are, and what medicines seem to help the most. Table 8 presents the percentage of patients who reported a symptom and were also bothered by it enough to want to take a medicine. Back to Top What are the medicines used to treat the common symptoms? There are many medicines available to treat the symptoms. Table 9 lists some of the commonly used medicines. Remember that each person is different and the choice of medicine to be used is best determined by the treating physician.
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